Inflammation associated with viral infections, such as influenza virus infection, is the cause of much morbidity and mortality. The severity of both seasonal and pandemic influenza virus infection has been associated with inflammation and the over-production of proinflammatory cytokines.
Inflammation is the complex biological response to stimuli including pathogens, such as viruses (Serhan and Ward, 1998, Molecular and Cellular Basis of Inflammation, Humana Press, Clifton, N.J.). Examples of plasma-derived mediators of inflammation include, among others, bradykinin, C3, C5a, Factor XII, Membrane attack complex (i.e., C5b, C6, C7, C8, C9), plasmin, and thrombin. Examples of cell-derived mediators of inflammation include, among others, histamine, IFN-γ, IL-1, IL-8, TNFα, leukotrienes, nitric oxide, and prostaglandins.
Toll-like receptors (TLRs) are a class of receptors that activate immune responses after recognizing molecules derived from pathogens. TLRs are pattern recognition receptors (PRR) that can recognize molecules broadly shared by pathogens. A number of TLRs (e.g., TLR7, TLR8, TLR9), along with other molecules (RIG-1, MDA), are known to recognize RNA from viruses, such as influenza virus and HIV (Meier et al., 2007, J. Virology 81:8180-8191). The activation of TLR leads to inflammation.
In addition to controlling inflammation occurring after infection, agents and methods are under development to prevent infection from occurring in the first place. One strategy for preventing infection, for example by preventing the transmission of infectious agents (e.g., HIV) during vaginal sex, is the deployment of topical, female-applied, microbicidal agent that can be applied directly to the genital tract to diminish the probability of acquiring or transmitting HIV. Candidate microbicides presently under development for intravaginal application include alkyl sulfate surfactants, chemokine co-receptor analogues and other compounds that specifically or non-specifically block virus-host cell interactions. Such microbicides may also be useful to block rectal transmission of viruses. An ideal microbicide would fulfill a number of criteria including having in vivo activity against both cell-free and cell-associated HIV, would also not adversely affect the protective integrity of vaginal and cervical mucosal epithelium.
The ability to interfere with the activation of TLRs, such as TLR7, TLR8 and TLR9, to diminish the severity of inflammation associated with viral infection will aid in diminishing the morbidity and mortality contributed by inflammation associated with viral infection. Moreover, the ability to interfere with the transmission of infectious agents, such as viruses, will also aid in diminishing the morbidity and mortality contributed by infection. To date, there are no compounds that effectively provide such interference. The present invention fulfills these needs.